HPAPIs from early development to full-scale manufacturing
Juliette Martin , scientific communication manager , and Michael Kleppinger , sales & marketing chief - BU Innovative , at Seqens share best practices and synthetic route considerations for delivering highly potent drugs
Highly potent drugs represent a growing proportion of medicines , including therapies in development and those commercially available . HPAPIs offer a range of benefits over conventional APIs , including high target specificity , retention ( in their active form ) within the body for longer durations and fewer side effects .
At present , more than 40 % of all drugs are highly potent in nature . Furthermore , 60 % of HPAPIs are in the oncology field , and as approximately one third of all new drug approvals are currently cancer medicines , which represents a substantial market opportunity . Other therapeutic areas where drugs may be highly potent include asthma , diabetes , cardiovascular disease , hormone imbalances and autoimmune disorders .
The demand for the capability and capacity to manufacture HPAPIs , particularly for CDMOs , is rising significantly . From lab to commercial scale , this article looks at some key considerations and best practices that are required for implementing the handling and manufacturing of these compounds .
Risk analysis
The EU regulatory guideline came into effect for all new pharmaceutical products on June 2015 , and for all existing pharmaceutical products on December 2015 . This guideline centres on the use of the acceptable daily exposure ( ADE ) and the operational considerations associated with implementation . 1
The ADE is defined as the dose of an API unlikely to cause adverse effects if an individual is exposed , by any route , at or below this dose every day over a lifetime . It is considered synonymous with the term permitted daily exposure ( PDE ).
The guidance states that APIs require an ADE . Hence , other substances such as starting materials , process intermediates and cleaning agents may benefit from an ADE . Problems in setting ADEs for these additional substances typically relate to toxicological data limitations precluding the ability to establish a formal ADE .
Established methodologies , such as occupational exposure limits ( OELs ) or bands ( OEBs ), can be used or adjusted as the availability of data for the API will increase throughout the drug development lifecycle . A compound is deemed to be potent in pharmaceutical terms if it has an eighthour , time-weighted average OEL of ≤10 µ g / m 3 ( Figure 1 ).
An OEB is a process intended to accurately assign chemicals into specific categories ( bands ), each
Figure 1 – OEBs & OELs
corresponding to a range of exposure concentrations designed to protect worker health . These bands are assigned based on a chemical ’ s toxicological potency and the adverse health effects associated with exposure to it . 2
Challenges for industrialisation
During process development studies , several technical challenges need to be addressed , due to the highly potent and potentially toxic nature of these substances . These include :
• Containment : HPAPIs must be handled in a highly controlled environment with stringent containment measures to prevent exposure to workers , the environment and the product itself
• Cross-contamination : There is a risk of cross-contamination when manufacturing HPAPIs because they are typically manufactured in the same facility as other products . This can occur during equipment cleaning , transfer operations and raw material handling
12 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981